Fundamental research on the treatment for pancreatic cancer by newly constructed oncolytic herpes simplex viruses

我们已经开发了一种条件复制型HSV-1载体（d120.surv），它是突变型HSV-1（d120）的改良版本，其中ICP 4由survivin启动子驱动。此外，我们还开发了另一种载体d120。survE，其中4f 2增强子包括在存活素启动子的上游。在胰腺癌细胞系中，Survivin启动子对397的激活依赖于Survivin mRNA的表达，且Survivin启动子可被辐射激活。在4f 2重链增强子蛋白的存在下，存活素启动子被辐射进一步激活。放射抗性细胞株Panc-1/Rad 15和AsPC-1/Rad 10的survivin蛋白表达增强，survivin启动子活性增强。在胰腺癌细胞中，d120的滴度。surv，d120. survE和HrR 3以时间依赖性方式增加;然而，在存活素阴性的HUVEC细胞中，d120的滴度。surv，d120. survE和HrR 3没有改变。通过d120.surv，d120。survE和HrR 3，存活胰腺癌细胞的数量以MOI依赖性方式减少。载体的溶瘤效果取决于每个癌细胞的存活素启动子的活性。

We have developed a conditionally replication competent HSV-1 vector (d120.surv), a modified version of the mutant HSV-1 (d120), in which ICP4 is driven by survivin promoter. Further, we have developed another vector, d120. survE, in which 4f2 enhancer is included upstream of survivin promoter. In pancreatic cancer cell lines, the activity of 397 by survivin promoter was dependent on the expression of the survivin mRNA, and the survivin promoter was activated by irradiation. In the presence of 4f2 heavy chain enhancer protein, the survivin promoter was further activated by irradiation. Radio-resistant cell lines, Panc-1/Rad15 and AsPC-1/Rad10, showed stronger expression of survivin protein and stronger activity of survivin promoter. In pancreatic cancer cells, the titer of d120. surv, d120. survE and HrR3 was increased in a time dependent manner ; however, in survivin-negative HUVEC cells, the titer of d120. surv, d120. survE and HrR3 was not changed. By d120.surv, d120. survE and HrR3, the number of viable pancreatic cancer cells decreased in a MOI dependent manner. The oncolytic efficacy of the vectors was dependent on the activity of survivin promoter of each cancer cell.